Abstract
Anti-angiogenic therapies were approved for different cancers. However, significant primary and secondary resistance hampers efficacy in several tumor types including breast cancer. Thus, we need to develop clinically applicable strategies to enhance efficacy of anti-angiogenic drugs.We report that anti-angiogenic therapies can induce upregulation of cyclooxygenase-2 (Cox-2) and of its product prostaglandin E2 (PGE2) in breast cancer models. Upon Cox-2 inhibition PGE2 levels were normalized and efficacy of anti-vascular endothelial growth factor receptor 2 (anti-VEGFR-2) antibodies and sunitinib was enhanced. Interestingly, both treatments exerted additive anti-angiogenic effects. Following Cox-2 inhibition, we observed reduced infiltration of tumors with cancer-associated fibroblasts (CAFs) and lower levels of pro-angiogenic factors active besides the VEGF axis including hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2). Mechanistic studies indicated that Cox-2 inhibition reduced PGE2-induced migration and proliferation of CAFs via inhibiting phosphorylation of Akt.Hence, Cox-2 inhibition can increase efficacy of anti-angiogenic treatments and our findings might pave the road for clinical investigations of concomitant blockade of Cox-2 and VEGF-signaling.
Highlights
Tumor angiogenesis represents an important hallmark of cancer [1, 2]
We report that anti-angiogenic therapies can induce upregulation of cyclooxygenase-2 (Cox-2) and of its product prostaglandin E2 (PGE2) in breast cancer models
In order to analyze whether increased expression of Cox-2 had functional consequences we subsequently determined prostaglandin (PGE2) levels and found that they were enhanced 1.7-fold in 4T1 tumors after anti-angiogenic therapy with 40 mg/kg DC101 and 5.2-fold after treatment with 60 mg/kg sunitinib (Figure 1E and F)
Summary
Significant efforts were made in the past 20 years to develop monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs), which are mainly targeting the VEGF pathway because this pathway was considered indispensable for tumor neovascularization [3,4,5]. These VEGF (receptor) inhibitors (VEGF(R)Is) include bevacizumab, aflibercept, sunitinib, pazopanib and sorafenib and were approved for the treatment of different cancers either as single agents or in combination with standard chemotherapy [5,6,7]. The possibility to increase efficacy of anti-angiogenic drugs at lower than maximum tolerated dose (MTD) levels of anti-angiogenic drugs would be desirable, because their side effects often require dose reductions in cancer patients [13]
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